Role of endoplasmic reticulum stress in acrolein-induced endothelial activation.
Acrolein is a ubiquitous environmental pollutant and an endogenous product of lipid peroxidation. It is also generated during the metabolism of several drugs and amino acids. In this study, we examined the effects of acrolein on endothelial cells. Treatment of human umbilical vein endothelial cells (HUVECs) with 2 to 10 microM acrolein led to an increase in the phosphorylation of eIF-2alpha within 10 to 30 min of exposure. This was followed by alternate splicing of XBP-1 mRNA and an increase in the expression of the endoplasmic reticulum (ER) chaperone genes Grp78 and Herp. Within 2-4 h of treatment, acrolein also increased the abundance and the nuclear transport of the transcription factors ATF3, AFT4, and CHOP. Acrolein-induced increase in ATF3 was prevented by treating the cells with the chemical chaperone - phenylbutyric acid (PBA). Treatment with acrolein increased phosphorylation of ERK1/2, p38, and JNK. The increase in JNK phosphorylation was prevented by PBA. Acrolein treatment led to activation and nuclear translocation of the transcription factor NF-kappaB and an increase in TNF-alpha, IL-6 and IL-8, but not MCP-1, mRNA. Increased expression of cytokine genes and NF-kappaB activation were not observed in cells treated with PBA. These findings suggest that exposure to acrolein induces ER stress and triggers the unfolded protein response and that NF-kappaB activation and stimulation of cytokine production by acrolein could be attributed, in part, to ER stress. Chemical chaperones of protein-folding may be useful in treating toxicological and pathological states associated with excessive acrolein exposure or production.
Haberzettl
Petra
P
Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
Vladykovskaya
Elena
E
Srivastava
Sanjay
S
Bhatnagar
Aruni
A
D000171:Acrolein / Q000008:administration & dosage / Q000633:toxicity*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D012326:RNA Splicing / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D000071717:X-Box Binding Protein 1
D016207:Cytokines; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004785:Environmental Pollutants; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D018832:Molecular Chaperones; D016328:NF-kappa B; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D000171:Acrolein